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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 140 RSC Advances Bioactive natural products derived from Mangrove-Associated Microbes Jing Xu 1 * 1 Key Laboratory of Protection and Development Utilization of Tropical Crop Germplasm Resources, Ministry of Education, College of Material and Chemical Engineering, Hainan University, Haikou 570228, P. R. China Manuscript Jing Xu obtained her BS and MS degrees from Hainan University. In 2006, she began her doctoral research with Professor Huashi Guan at the College of Medicine and Accepted Pharmaceutics, Ocean University of China. In 2007, she continued with her doctoral research in a group working with Professor Peter Proksch and received her PhD degree in 2010 at Heinrich-Heine-Universität Düsseldorf, Germany. She joined the faculty at Hainan University after her graduation where she is currently an Associate Professor of Advances Pharmaceutical Chemistry. Simultaneously, she undertook a postdoctoral appointment at Nanjing University, with Professor Renxiang Tan from 2011 to 2014. Her research RSC interests are focused on natural products originating from endophytic microbes and medicinal plants. * To whom correspondence should be addressed. Tel: ++86 898 6627 9226; Fax: ++86 898 6627 9010; Email: [email protected] RSC Advances Page 2 of 140 Abstract This review summarizes new findings concerning the sources and characteristics of various natural products that can be extracted from mangrove-associated microbes over the past three years (January 2011-December 2013). The natural products are discussed with a focus on bioactivity, highlighting the unique chemical diversity of these metabolic products. Keywords Mangrove-associated microbes, actinomycetes, bacteria, fungus, biomolecules, Manuscript polyketides, terpenoids, nitrogenated compounds, biological activities, synthesis, biosynthetic origin Accepted Advances RSC Page 3 of 140 RSC Advances Contents 1. Introduction 2. Actinomyces-derived molecules 2.1. Terpenoids 2.2. Nitrogenated compounds 3. Bacterial metabolites 4. Fungal metabolites 4.1. Polyketides 4.1.1 Coumarins Manuscript 4.1.2 Isocoumarin derivatives 4.1.3 Chromones 4.1.4 Flavonoids 4.1.5 Quinones Accepted 4.1.6 Xanthones 4.1.7 Phenol and phenolic acids 4.1.8 Lactones 4.1.9 Miscellaneous polyketides 4.2. Terpenoids Advances 4.2.1 Sesquiterpenes 4.2.2 Diterpenes RSC 4.2.3 Sesterterpenoids 4.2.4 Triterpenes 4.2.5 Meroterpenes RSC Advances Page 4 of 140 4.3. Nitrogenated compounds 4.3.1 Amines and Amides 4.3.2 Isoquinolines 4.3.3 Quinolines 4.3.4 Indole derivatives 4.3.5 Quinazoline derivatives 4.3.6 Peptides 4.3.7 Miscellaneous nitrogenated derivatives 4.4. Steroids Manuscript 5. Concluding remarks 6. References Accepted Advances RSC Page 5 of 140 RSC Advances 1. Introduction Microorganisms from special ecological niches such as the mangrove endosymbionts are a rich source of diverse and structurally unique bioactive natural products. Microbes inhabiting mangrove ecosystems adapt to frequent and sporadic environmental changes, including high salinity, low oxygen, nutrient limitation, tidal gradients, high temperatures, excessively high light, and drought 1. The warm and damp conditions result in an active microbial community, which can act as an effective selector for metabolic pathway adaptations via generation of unique functional metabolites of pharmaceutical importance. Manuscript Mangrove forests are complex ecosystems that harbor diverse groups of microorganisms including actinomycetes, bacteria, fungi, cyanobacteria, microalgae, macroalgae and fungus-like protozoa. In the tropical mangrove microbial community, bacteria and fungi constitute 91% of the total microbial biomass, whereas algae and Accepted protozoa represent only 7% and 2%, respectively. Although the mangrove ecosystem has extensive microbial diversity, culture-dependent technologies reveal only a small percentage (<1 %) of the microbial community while 99 % of the microorganisms remain undiscovered. Among the isolated microbes, less than 5% of species have been presently chemically estimated, and these include the actinomycetes, bacteria and fungi. The Advances advent of modern techniques provides the opportunity to find novel metabolites 2. Mangrove associated microbial natural products have been the subject of several RSC review articles. Advances in the chemistry and bioactivity of fungi from mangroves have been reviewed periodically in Natural Product Reports by Blunt and his co-workers 3, 4 . Wang et al. reviewed the studies on structure and bioactivity of metabolites isolated from RSC Advances Page 6 of 140 mangrove-derived fungi in the South China Sea 5. Prof. Proksch’ group compiled a comprehensive review detailing a decade of studies on potential of mangrove-derived endophytic fungi as promising bioactive natural products 6, 7. Our previous review discussed the role of these endophytic fungi as a major source of antimicrobial agents. These fungi produce a wide range of medicinal compounds, including antitumor, neuroprotective, antioxidant, anti-AChE, anti-BKCa channel agents, and 348 molecules were discovered before 2011 8. However, 464 new metabolites have been discovered recently; therefore, we describe here the source, chemistry, and biology of the newly discovered biomolecules Manuscript from the mangrove-associated microbes. We also summarize the chemical synthesis and the biosynthetic relationship of metabolites. All relevant studies focusing on known secondary metabolites in terms of bioactivity, the source of the microorganism, and the location of collection are examined, and particular emphasis is given to their potential use Accepted as drug leads. The running titles are presented in the following order: actinomycetic, bacterial, and fungal producers with structures classified within a biogenetic context as polyketides, terpenes, and nitrogenated compounds. Bioassays showed that the antitumor, anti-influenza A H1N1, anti-enzyme, anti- or activate- subintestinal vessel plexus and brine shrimp lethality activities were the most notable bioactivities of secondary Advances metabolites isolated during 2011-2013 . Possible biogenetic relationships between several alkaloids, quinones, phenols, lactones, sesquiterpenes, sesterterpenoids, and meroterpenes RSC are discussed. The biomacromolecules originating from the title microbes were not within the scope of this review. The Metabolites Name Index in conjunction with the Microbial and Host Source Index, the Bioactivity Index and the Leading References on isolation in Page 7 of 140 RSC Advances the accompanying Tables, will help understand the fascinating chemistry and biology of naturally occurring mangrove-associated microbial metabolites. 2. Actinomyces-derived molecules Due to the high rediscovery rate of known compounds from Actinomycetes , there has been a renewed interest in the development of new antimicrobial agents from this species. These compounds can help combat the increasing number of multidrug-resistant human pathogens 9. Mangrove-derived actinomycetes are a potentially vast resource of structurally diverse natural products with unusual biological activity. Streptomyces are Gram-positive bacteria known for the production of an enormous variety of biologically Manuscript active secondary metabolites, including antibiotics, immunosuppressants, and anticancer agents and have been become the focus of antibiotic research in the past three years. 2.1. Terpenoids Eudesmene sesquiterpenes are proposed to be originated from further cyclization of Accepted the monocyclic germacranes 10. They are most abundant as eukaryotic secondary metabolites and may be referred to as selinanes, commonly metabolized by a variety of plants, such as Inula japonica 11, Blumea balsamifera 12, and Nectandra cissiflora 13. The only examples from prokaryotes are the recently described 14 selina-4(14),7(11)-diene-8,9-diol from a marine Streptomyces sp. ; and Advances 1,6,11-eudesmanetriol and 11-eudesmene-1,6-diol from an endophytic Streptomyces sp. 15 of Drymaria diandra . Five new members of this family, kandenols A-E ( 1−5), were RSC characterized from a culture filtrate of endophytic Streptomyces sp. HKI0595 isolated from Kandelia candel (L.) (Xiamen, Fujian, China) using an HPLC-MS hyphenated system. The configuration of these eudesmenes was rigorously established by a RSC Advances Page 8 of 140 combination of the Mosher method and comparison of CD spectra with α-rotunol and β-rotunol. Hydroperoxide moieties are relatively rare in compounds 3 and 4. Metabolite